抗心律失常药物胺碘酮与钠通道 Na1.5 的相互作用取决于细胞外 pH 值。
Interaction of the antiarrhythmic drug Amiodarone with the sodium channel Na1.5 depends on the extracellular pH.
机构信息
Laboratory of CardioBiology, Department of Biophysics, Paulista School of Medicine, Federal University of Sao Paulo, Brazil.
Laboratory of CardioBiology, Department of Biophysics, Paulista School of Medicine, Federal University of Sao Paulo, Brazil; Department of Physiology, Federal University of Sergipe, São Cristóvão, Brazil.
出版信息
Eur J Pharmacol. 2023 Dec 5;960:176127. doi: 10.1016/j.ejphar.2023.176127. Epub 2023 Oct 17.
INTRODUCTION
Amiodarone (AMD) is a clinically used drug to treat arrhythmias with significant effect upon the cardiac sodium channel Na1.5. AMD has a pKa of 6.56, and changes in extracellular pH (pHe) may alter its pharmacological properties. Here we explored how changes in pHe impacts the pharmacological properties of AMD upon human-Na1.5-sodium-current (I) and in ex vivo rat hearts.
METHODS
Embryonic-human-kidney-cells (HEK293) were used to transiently express the human alpha-subunit of Na1.5 channels and the isolated heart of Wistar rats were used. Patch-Clamp technique was deployed to study I and for electrocardiogram (ECG) evaluation the ex vivo heart preparation in the Langendorff system was applied.
RESULTS
The potency of AMD upon peak I was ∼25x higher in pHe 7.0 when compared to pHe 7.4. Voltage dependence for activation did not differ among all groups. AMD shifted the steady-state inactivation curve to more hyperpolarized potentials, with similar magnitudes for both pHes. The recovery from I inactivation was delayed in the presence of AMD with similar profile in both pHes. Interestingly, the use-dependent properties of AMD was distinct at pHe 7.0 and 7.4. Finally, AMD was able to change the ex vivo ECG profile, however at pHe 7.0+AMD a larger increase in the RR and QRS duration and in the QT interval when compared to pHe 7.4 was found.
CONCLUSIONS
The pharmacological properties of AMD upon Na1.5 and isolated heart preparation depends on the pHe and its use in vivo during extracellular acidosis may cause a distinct biological response in the heart tissue.
简介
胺碘酮（AMD）是一种临床上用于治疗心律失常的药物，对心脏钠通道 Na1.5 有显著影响。AMD 的 pKa 为 6.56，细胞外 pH 值（pHe）的变化可能改变其药理学特性。本研究探讨了 pHe 的变化如何影响 AMD 对人源 Na1.5 钠电流（I）的药理学特性，以及在离体大鼠心脏中的作用。
方法
利用瞬时表达人源 Na1.5 通道α亚单位的胚胎肾细胞（HEK293）和离体大鼠心脏，采用膜片钳技术研究 I，并应用 Langendorff 系统中的离体心脏标本进行心电图（ECG）评估。
结果
与 pHe 7.4 相比，AMD 对 I 峰值的作用强度在 pHe 7.0 时约高 25 倍。激活的电压依赖性在所有组之间没有差异。AMD 使稳态失活曲线向更超极化的电位移动，两种 pH 值下的幅度相似。在 AMD 存在的情况下，I 失活的恢复被延迟，两种 pH 值下的曲线相似。有趣的是，AMD 的使用依赖性特性在 pHe 7.0 和 7.4 时有所不同。最后，AMD 能够改变离体心脏的 ECG 谱，但在 pHe 7.0+AMD 时，RR 和 QRS 持续时间以及 QT 间期的增加幅度大于 pHe 7.4 时。
结论
AMD 对 Na1.5 和离体心脏标本的药理学特性取决于 pHe，其在细胞外酸中毒时体内的应用可能会在心脏组织中引起不同的生物学反应。
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